Staphylococcus aureus is an opportunistic pathogen that colonizes the skin (primarily the anterior nasal vestibule) of as many as 1 out 4 individuals without causing clinical disease symptoms. Humans are either persistently or intermittently colonized or never colonized with S. aureus i.e., defined as carriers, intermittent carriers or non-carriers. An individual's carriage status affects their likelihood of becoming infected and the nature of their immune response by S. aureus exposure. In addition, carriage status affects the severity of the infection(s) that range from minor skin infections to lethal infections associated with abscess formation, endocarditis and pneumonia. Certain antibiotics are available for the treatment of S. aureus-mediated disease, but the number of antibiotic-resistant strains is increasing rapidly. S. aureus is one of the most common causes of modern bacterial infections, in part due to increasing resistance to antibiotics and the recent emergence of infections caused by Community-Associated MRSA strains (CA-MRSA). In 2005, there were 94,360 invasive cases of MRSA in the United States, 18,650 resulted in death (incidence rate of 31.8/100,000 persons) much higher than S. pneumoniae and H. influenzae. The changing epidemiology of infections caused by S. aureus and increased antibiotic resistance necessitates the development of novel treatment modalities. Host susceptibility to S. aureus carriage status is at least partially under the control of underlying genetic factors. Their identification would provide targets for developing intervention strategies e.g., identification of novel pathways associated with carriage or genes associated with susceptibility will allow for the development of new interventions to eliminate carriage or treat infections. We will shortly complete genome-wide genotyping on 1000 nondiabetic and 1000 Type-2 diabetic Mexican-Americans from Starr County, Texas using the Affymetrix 6.0 platform. We have recently piloted procedures for determining carriage strains in this population and propose to determine S. aureus carriage status for 800 of the controls and 600 of diabetes cases for whom we will have nearly 1 million SNPs and 1 million copy number variants to carry out the proposed studies. Identification of these SNPs/genes will improve risk prediction and shed light on novel biological pathways bridging health and disease. It will also allow determining the role/interaction of Type-2 diabetes and S. aureus carriage/disease susceptibility. Success of genome-wide association studies depends on innovative and rigorous data analysis and replication in independent samples. We will use a combination of computer science- based informatics and statistical methods to prioritize genes and regions for follow-up. Understanding the genetics of susceptibility or resistance to this organism shall significantly accelerate and improve vaccine design strategies e.g., identification of novel pathways associated with carriage or genes associated with susceptibility will allow for the development of new interventions to eliminate carriage or treat infections.